In the present world, along with a high-speed development and raising living standards, people intake excessive fat and protein which result in global occurrence of the metabolic syndrome characterized by obesity, insulin resistance (Type II diabetes), lipid metabolic disorder and hypertension. These represent great threats to human health. In addition to the individual's genetic characteristics, age, sex, physiological nature, nutritional status, diet habit, etc., the metabolic syndrome is associated with imbalance in lipid metabolism, energy and carbohydrate metabolism in vivo. Thus, an effective method of treating the metabolic syndrome is a therapeutic regime aimed to maintain or restore balance in vivo in energy, fat and carbohydrate. As nuclear receptors (NRs) play a key role in maintenance of balance in vivo in energy, lipids and carbohydrates within a cell, as well as within whole individual's body, they become a focus of researches. Only when being activated by various physiological ligands (e.g., saturated fatty acids, unsaturated fatty acids, metabolites thereof, and various synthetic compounds), can the nuclear receptor regulate transcription systems of responsive genes, thus exert its physiological activity (Kasuga, J. et al., Bioorg. Med. Chem. 2007, 15, 5177-5190).
Among the nuclear receptor families, peroxisome proliferator activated receptors (PPARs) have attracted peoples' attention for more than ten years, which are nuclear transcription factors activated by their ligand and which act as a crucial regulatory factors in the metabolic syndrome (Guan, Y. J. Am. Soc. Nephrol, 2004, 15, 2801-2815). Therefore, PPARs play an important role in the genesis, development and control of diseases such as insulin resistance, impaired glucose tolerance, Type II diabetes, obesity, hyperlipidemia, hypertension, angiocardiopathy, artherosclerosis, etc.
PPARs are classified into three subtypes: PPARα, PPARδ and PPARγ, which regulate expression of the gene by binding to specific DNA sequence of a gene (Berger, J. et al., The Journal of Biological Chemistry, 1999, 274 (10), 6718-6725). PPARα is mainly expressed in the liver, heart, intestinal tract, kidney and macrophage, and, after being activated, can increase the metabolism of fatty acids, alleviate the Inflammatory response in macrophages, and reduce low density lipoprotein cholesterol; PPARγ is expressed in the adipocyte, placentoma and other tissues, and, after being activated, can not only lower the blood glucose level and increase the insulin sensitivity, but also play a key role in lipid metabolism, cytokine antagonization, anti-inflammation, immuno regulation and blood pressure regulation, etc. (Kasuga, J. et al., Bioorg. Med. Chem. 2007, 15, 5177-5190). In contrast to the other two subtypes, the physiologic function of the PPARδ is not clear up to now.
However, it has been shown in recent studies on animal models for pharmacology experiments that, the PPARδ can increase the fatty acid catabiosis and energy uncoupling in adipose tissue and muscle, and can suppress the macrophage-originated inflammation. Due to various functions in controlling gaining weight of human body, enhancing body's durability, increasing the insulin sensitivity and improving artherosclerosis, the ligands for the PPARδ may be an effective medicament for the treatment of hyperlipidemia, obesity, insulin resistance, and artherosclerosis.
At present, none of PPARδ receptor agonist agents are commercially available as a medicament. Among the present researches on the PPARδ agonists, clinical research on GW501516 developed by GlaxoSmithKline has shown that GW501516 may increase the level of high density lipoprotein (HDL) cholesterol up to 80%, lower the level of low density lipoprotein (LDL) cholesterol up to 29%, decrease the level of triglyceride (TG) up to 56%, decrease the level of insulin up to 48% (Oliver, W.; Jr.; Shenk, J. L. et al, Natl. Acad. Sci. U.S.A. 2001, 98, 5306-5311). Thus, it is believed that GW501516 can become an effective medicament for the treatment of obesity and cardiovascular diseases (WO01/00603A1, Bioorg. Med. Chem. Lett. 2003, 13, 1517). However, GW501516 project has been now temporarily suspended due to unfavorable results from its Phase II clinical trial.
Thus, there is an urgent need for providing a novel compound which has an agonisting action on peroxisome proliferator-activated receptor subtype δ (PPARδ) and a much better ability of regulating blood lipids than that of GW501516.